2-(1, 4-benzodioxan) methyl derivatives of amino-lower fatty acid amides and preparation thereof



United States Patent 2-(1,4-BENZODIOXAN)METHYL DERIVATIVES OFAMINO-LOWER FATTY ACID AMIDES AND PREPARATION THEREOF Daniel Bovet andGiovanni Battista Marini-Bettolo, Rome, Italy, assignors of fifty percent to Fondazione Emanuele Paterno, Rome, Italy, an Italianorganization No Drawing. Application January 29, 1954,

' Serial No. 407,144

Claims priority, application Italy February 13, 1953 21 Claims. (Cl.260-41403) This invention relates to certain 2-(1,4-benzodioxan)- methylderivatives of amino-lower fatty acid amides and to the preparation ofthe same.

More particularly, the new compounds provided by our invention arederivatives of amino-lower fatty acid amides bearing a 2-(1,4-benzodi0xan)methyl radical on either the amino nitrogen or theamide nitrogen which have the structural formula where R is a member ofthe class consisting of hydrogen and lower alkyl radicals, Z is analpha-oxo-lower alkylene radical, and -N=B is a member of the groupconsisting of the amino radical and lower alkylamino, (di-lower alkyl)amino, piperidino, lower alkylpiperidino, morpholino, loweralkylmorpholino, pyrrolidino, and lower alkylpyrrolidino radicals.

The alpha-oxo-lower alkylene radical Z in the formula set forthhereinabove contains at least two carbon atoms and preferably containstwo, three, or four carbon atoms; the oxo-bearing carbon atom of Z isalpha (adjacent) to either one of the two nitrogen atoms connected by Z.Equivalently, Z can be described as having the structure -COCnH2n where-CnH2n is a divalent alkylene radical in which n is one of the integersl, 2, or 3 and wherein the oxygen-bearing alpha carbon atom is attachedto one of the amino radical N=B and 2-(1,4-benzodioxan)methylamino inour compounds and another carbon atom of the COCnH2ngroup is attached tothe other amino radical. By way of illustration, the divalent radical Zcan be -CO-CH2, CO-CH2CH2-, COCH(CH3)-, COCH2-CH(CH3), COCH2CH2CH2, andthe like.

The new compounds of our invention are useful as sympatholytic agents,being antagonists of epinephrine and similar sypathomimetic amines. Aparticular advantage aiforded by our new compounds is the relatively lowdegree of undesirable effect on the central nervous system as comparedwith the sympatholytic agents previously available.

By the term lower alkyl employed above in the definitions of R and N=Band elsewhere in this specification, we mean to indicate alkyl radicalsof low molecular weight, as methyl, ethyl, propyl, isopropyl, butyl, andthe like. We particularly prefer the lower alkyl radicals containing 1-4carbon atoms.

The radical N=B includes the amino radical NH2, lower alkylaminoradicals having the formula --NHR (di-lower alkyl)amino radicals havingthe formula NR R and saturated 56 membered heterocyclic tertiary-aminoradicals such as piperidino, pyrrolidino, morpholino, and such cyclicamino radicals bearing a lower alkyl group R for exampleZ-methylpiperidino, 2- ethylpyrrolidino, 3-ethylmorpholino, and thelike. The lower alkyl radicals R R and R preferably contain 1-4 "icecarbon atoms and may be identical with, or different from, each otherand the previously defined radical R when it represents lower alkyl.

It will be appreciated from the foregoing description that our inventionembraces Z-(carbamylalkylaminomethyl)-1,4-benzodioxanes having thestructural formula I and 2-(aminoacylaminomethyl)-l,4-benzodioxanshaving the structural formula II Our new compounds of formula I aboveare prepared by interacting together a halo-lower fatty acid amidehaving the formula halogen CnH2nCON=B and a 2- (aminoor loweralkylaminomethyl)-1,4-benzodioxan, or by interacting a2-(halomethyl)-1,4-benzodioxan and an amino-lower fatty acid amidehaving the formula H-N(R)CnH2n-CON=B, as illustrated by the followingequation:

0 H C -OHzY hydrogen halide where one of Y and Y is halogen, preferablychlorine or bromine, and the other is HN(R)-. In each instance, thereaction is readily carried out by heating the reactants together forseveral hours or for such time as is necessary to complete the reaction.It is usually advantageous to carry out the reaction in the presence ofa base, for example by employing the amine reactant in excess of therequired equivalent amount or by adding an alkali metal hydroxide suchas sodium hydroxide, to facilitate the removal of the hydrogen halidewhich is produced.

Our new 2-(aminoacylaminomethyl)-1,4-benzodioxans of formula II aboveare readily obtained by interacting a 2- (aminoor loweralkylamino-methyl)-l,4-benzodioxan with a halo-lower fatty acyl halideor acid anhydride and treating the resulting product with an aminatingagent having the formula H'N=B. Thus, for example, when a halo-lowerfatty acyl halide is employed as the acylat- The 2- [N-(halo-lower fattyacyl)aminomethyl]-1,4- benzodioxans obtained as intermediate products inthis process are substances having an oily or wax-like consistency whichdecomposewhen distilled, and it is therefore usually advantageous toemploy these intermediate products without purification for theamination step. In general, we have found that it is most convenient toemploy chloro or bromo-lower fatty acyl chlorides or bromides as theacylating agent in this process.

The Z-(amino or lower alkyl-aminomethyl)-1,4-benzodioxans which areuseful in the preparation of the compounds of our invention" are readilyobtained by interacting 2-chloromethyl-1,4-benzodioxan with ammonia or alower alkylamine. This reaction is very conveniently carried out byheating the 2-chloromethyl-1,4-benzodioxan in an autoclave with analcoholic solution of the aminat'ing agent in excess of the amountrequired byftheory.

Our invention is illustrated by the following examples Without, however,being limited .theretof In these examples, for purposes of convenienceand brevity in setting forth the structural formulas of the respectiveproducts described therein, the symbol A is employed to designate the2-(l,4-benzodioxan)methyl radical having the formula A mixture of 35.8g. of 2-methylaminomethyl-1,4-benzodioXan (B. P. 124 C. at 4 mm.) and15.'0'g.'of N,N- diethyl-2-chloroacetamide was' heated for twenty-fourhours at 100 C. The reaction mixture was then suspended in water,rendered alkaline by treatment with a 25% aqueous solution of potassiumcarbonate, and the alkaline mixture was extracted with chloroform. Thechloroform solution thus obtained was dried over anhydrous potassiumcarbonate and, after removal of the drying agent, the chloroform wasremoved from the solution by evaporation. The residue thus obtained wasdistilled at reduced pressure to yield 2-[N-methyl-N-(N,N-diethylcarbamylmethyl)aminomethyl] 1,4 benzodioxan, which boiled atl69170 C. at 0.7 mm. and had n 1.5216.

The same product described above is obtained by heating a mixture of2-chloromethyl-1,4-benzodioXan and N,N-diethyl-2-(methylamino)acetamide.

' EXAMPLE 2 p 2- [N tetramethylenecarbamylmethyl aminomethyl1,4-benzdioxan CHz-CH:

A-NH-CHz-C O-N The above designated compound is obtained by interacting2-aminomethyl-1,4-benzodioxan (B. .P. 127137 C. at4mm.) andN-(chloroacetyl)pyrrolidine.

2- [N (2 -carbamylethyl aminomethyl 1 ,4-benzodioxan A-NHCH2CH2CO-NH2The above designated compound is obtained by interactingZ-aminomethyl-1,4-benzodioxan and 3-bromopropionamide.

EXAMPLE 4 2-{NEZ-(N-methylcarbamyl)ethyl]aminomethyl}- 1,4-benz0dioxanANHCH2CHt,'CO-NHCH3 The above-designated compound. was preparedbyinteracting 2 aminomethyl-1,4-benzodioxan and N-ethyl-3-chloropropionamide. The product thus obtained boiled at 203-228 C. at0.4 mm.

EXAMPLE 7 2-{N-[2(N,N-diethylcarbamyl) ethyl] aminomethyl}-1,4-benzodi0xan ANH-CH2-CH2CON (C2H5 2 Theabove-designated compound wasprepared by interacting 2-aminornethyl-1,4-benzodiogran and N,N-diethyl-I 3-chloropropionamide. The product thus obtained boiled at '-1s5 C. at0.15 and had 11 1.5345.

, EXAMPLE8 2 -{N -methyl-N [2 (N -methylcz zrbamyl ethyl amino-'methyl}-1,4-benz0dioxan A-N-C H2o Hz-C ONH-.-C H;

The above-designated compound was prepared by interactingZ-methylaminomethyl-1,4-benzodioXan and N- methyl-3-chloropropionamide.The product thus obtained boiled at 179-186 C. at 0.2 mm. and had n1.5436.

1 EXAMPLE 9 Z-{N -me'thyl-N [2- (N ,N -d imezhylcarbamyl ethylaminomethyl}-l,4-benz0di0xan AN-CHzCHcOON(OHa)2 H3 The above-designatedcompound was prepared by interactingZ-m'ethylaminomethyl-1,4-benzodioxan and N,N- dimethyl3-chloropropionamide. The product thus obtained boiled at 167-169 C. at0.2 mm. and had 11 1.5327.

' EXAMPLE 10 2-{N-methyl-N-[2-(N-ethylcarbamylethyl)amino-.methyl}-1,4-benz0,dioxan ANCHzCHg-C O'-NHCZH above-designated compoundwas prepared by interacting 2-methylaminomethyl-1,4-benzodioxan and. N-ethyl3-chloropropionamide. The product thus obtained The'above-designated compound-was prepared by in' teracting 2-methylaminomethyl-1,4-benzodioxan and N,N- diethyl-3-chloropropionamide.The product thus obtained boiled at 167-169" C. at 0.2 mm. and had'n'1.5235.

EXAM LE 12 Z-{N-methyl N [2 (pentamethylenecarbamyl)ethyl]-aminomthyG-I,4-benz0di0xan CH2CI-Iz A-NCH2-CHr-O O N CH2 v 113 out-0E2The above-designated compound is obtained byinteractingZ-methylaminomethyl-l,4-benzodioxan: and .N-( 3chloropropionyl)piperidine. I A

EXAMPLE 13 j Z-{N-methyl N [2(N-propylcarbamyl)ethyl1zzminomethyl}-1,4-benz0di0xan Theabove-designated compound was prepared by interacting 2methylamin'omethyl-1,4-benzodioxan' andN-isopropyl-3-chloropropionamide. The product thus obtained boiledat'169179 C. at 0.2 mm. and'had r15 1.5273.

EXAMPLE 15 Z-{N-ethyl-N- [Z-(N-methylcarbamyl) ethyl]aminomethyl}-1,4-benzodi0xan EXAMPLE 16 Z-{N-ethyl-N [2- (N-ethylcarbqmyl ethyl ominomethyl}-1,4-benz0dioxan' The above-designatedcompound was prepared by interacting 2(ethylaminomethyl)-1,4-benzodioxan and N-ethyl-3-chloropropionamide. Theproduct thus obtained boiled at 180186 C. at 0.4 mm. and had n 1.5290.

XAMPLE 17! Z-{N-czh yZ-N- [2- (3-oxapentamcthylenecarbamyl)ethyl]amin0m'ethyl}-1,4-benzodioxan The above-designated compound isobtained by interacting 2-(ethylaminomethyl)-1,4-benzodioxan and N- 3-chloropropionyl)morpholine. f

6 EXAMPLE 1s 2-{N-pr0pyl-N-[Z-(N-methylcarbamyl)ethyl]- aminomethyl}-1,4-benz0di0xan A1 |IOHzCHzO ONH- CHa CHz-CH2CH3 The above-designatedcompound was prepared by interactingZ-(propylaminomethyl)-1,4-benzodioxan (B. P. 134 C. at 2 mm.) andN-methyl-3-chloropropionamide. The product thus obtained boiled at185-192 C. at 0.2 mm. and had n 1.5305.

' EXAMPLE 19 The above-designated compound was prepared by interacting2-(isopropylaminomethyl) 1,4 benzodioxan (B. P. 134-136 C. at 4 mm.) andN-methyl-3-chloropropionamide. The product thus obtained boiled at -190C. at 0.1 mm. and had 11 1.5320.

EXAMPLE 20 2- [N -methyl-N N ,N -diethylaminoacetylaminomethyl]-1,4-benzodioxan 3.6 g. of-2-methylaminomethyl-1,4-benzodioxan was dissolved in 50 ml. of,8%aqueous sodium hydroxide solution,. and to this solution there was added2.3 g. of chloroacetyl chloride. After the reaction had terminated, theoil which had separated from the mixture was extracted with chloroform,the chloroform solution was agitated in contact with water-,and thechloroform solution was then separated and dried over sodium sulfate.After the removal of the drying agent, the chloroform .was removed fromthe solution by evaporation, thus yielding an oily residue. Since it wasfound that this product, which was2-[N-methyl-N-(chloroacetyl)aminomethyl]- 1,4-benzodioxan, was sensitivetoheat and tended to decompose if distilled, it was treated directlywithout purification with diethylamine, the mixture being heated inaiclosed'tube on a water bath. The amination product thus obtained wasdissolved in water, the solution .W'as rendered alkaline by treatmentwith 20% aqueous sodium hydroxide solution, and the mixture was thenextracted with chloroform. The chloroform was removed from the solutionby evaporation and the residue thus obtained was distilled under reducedpressure. There was thus obtained 2-[N-rnethyl-N-(N,N-diethylaminoacetyl amino methyl]-1,4-benzodioxan as acolorless oil which boiled at 153163 C. at 0.2 mm. and had n 1.5285. Thecompound was fluorescent under Woods light.

The intermediate 2- [N-methyl-N-(chloroacetyl)aminomethyl]-1,4-benzodioxan is also obtained when chloroacetylanhydride is employed instead of chloroacetyl chloride in the first stepofthis example.

EXAMPLE 21 I 2 {N [(2 methylpip ericlino )acetyl]aminomethyl}-1,4-benzoa'ioxan CHg-CH2 The above-designated compound is obtained byinteracting 1 2-aminomethyl-1,4-benzodioxan and chloroacetyl chloride.followed by treatment of the resulting 2-[N- .(chloroacetyl)aminomethyl]1,4 benzodioxan with 2- methylpiperidine.

EXAMPLE 22 2-{N -methyl-N [3- (N ,N-diethylamino)propionyllaminomethyl}-1,4-benzdi0xan A-N-O OO Hz-C HaN(C 2H5) 1 C HaEmploying a procedure similar to that described above in Example 21,2-methylaminomethyl-1,4-benzodioxan was interacted with3-chloropropionyl chloride to yield 2 [Nmethyl-N-(3-chloropropionyl)aminomethyl]-l,4- benzodioxan, which had awax-like consistency, and this product was interacted with diethylamine.There was thus obtained Z-{N-methyl-N-[3-(N,N-diethylamino)propionyl]aminomethyl}-1,4-benzodioxan in the form of a colorless oilwhich boiled at 178+182 C. at 0.4 mm. and had 11 15300.

EXAMPLE 23 2- [N-ethyl-N-(3-m0rph0linobutyryl) aminomethyl] 1,4-benzodioxan O Hr-CH: A-N-C worn-0 H-N 2115 Ha CHu-C:

The above-designated compound is obtained by interacting 2-(ethylaminomethyl)-l,4-benzodioxan and 3- chlorobutyryl chloride, andtreating the resulting 2-[N- ethyl-N- 3-chlorobutyryl) aminomethyl]-1,4-benzodioxan with morpholine.

In addition to the above examples, the following compounds are alsoillustrative of our invention:

2 [N butyl-N-(N-methyl-N ethylcarbamylmethyl)aminomethyl]-1,4-benzodioxan, having the formula ANOH2-C ON Hz)a Ha02115 2 {N '[l methyl-2-(N-methyl-N-propylcarbamyl)-ethyl]-aminomethyl}-1,4-benzodioxan, having the formula 2 {N methyl N[2-(2-ethylpyrrolidinocarbamyl)- ethyl]aminomethyl}-1,4-benzodioxan,having the formula 2 {N ethyl-N-[4-(N-methyl-N-butylamino)butyryl]-aminomethyl}-1,4-benzodioxan, having the formula A-N-C o-c H2.CH2-CH3N2H5 CH2CHzCH2-CH3 2 [N-propyl-N- 3-aminopropiony1) aminomethyl]-1,4-

benzodioxan, having the formula ANC OC Hz-C Hz-NH:

Hn-CHzCHs erties of the free amine forms with which they are equivalent.

- We claim: 1 I 1. A compound having the formula where R is a member ofthe class consisting of hydrogen and lower alkyl radicals, Z is analpha-oxolower alkylene radical, and -N =B is a member of the groupconsisting of the amino radical and lower alkylamino (di-loweralkyl)amino, piperidino, lower alkylpiperidino, morpholino, loweralkylmorpholino, pyrrolidino, and lower alkylpyrrolidino radicals.

2. A 2 {N [2f- (N,N-dialkylcarbamyl)ethyllaminomethy1}-1,4-benzodioxanhaving the formula where R .and R are loweralkyl radicals.

3. A 2{N-[2-(N-loweralkylcarbamyl)ethyllaminomethyl}-1,4-benzodioxanflhaving the formula og/fiiv (I o-o Irr-Nn-oHr-cm-w 0-NH-R where R iis a lower alkyl radical.

4. A Z-{N-lower alkyl-N:[2-(N,N-diloweralkylcarbamyD-ethyl]aminomethyl}-1,4-benzodioxan having the v,.

where R, R and R are lower alkyl radicals.

5. A 2-{N-lower alkyl-N-[Z-(N-lower alkylcarbamyD-ethyl]aminomethy1}-1,4-benzodioxan having the formula where R anaR are16ml: alkyl radicals.

6. A 2-[N-(N,N-di-lower alkylcarbamylmethyl)aminomethyl]-1,4-benzodioxan having the formula where R, R and R? are.lower alkyl radicals.

7. A 2 [N- lower alkyl-N-(N-loweralkylcarbamylmethyl)-aminomethyl]-l,4-benzodioxan having the formula I iC- CH1-IIT-CHr-C O-NHR1 whefeRandRlimre loweralkylradicals. 8. A2-[N-(N-1ower alkylarhinoacetyhaminomethyllwhere R is a lower alkylradical.

9. A 2-[N-lower alkyl-N-(N,N- di -lo weralkylaminoacetyl)aminomethyl]-1-,,4-benzodioXan having the formula Iwhere R, R and R are lower-alkyl radicals.

10. A 2-{N-[3-(N-loweralkylamino)propionyl]amino-methyl}-1,4-benzodioxan having the formulawhere R is a lower alkyl radical.

11. A 2-{N-lower alkyl-N-[3-(N,N-di-lower alkylamino) -propionyl]aminomethyl}-1,4-benzodioxan having where R, R and R are lower alkylradicals.

12. A process for the preparation of aZ-(carbamylalkylaminomethyl)-l,4-benzodioxan having the formula where Ris a member of .the class consisting of hydrogen and lower alkylradicals, n is an integer of the group 1 to 3 inclusive, and N=B is amember of the group consisting of the amino radical and loweralkylamino, (cli-lower alkyl)amino, piperidino, lower alkylpiperidino,morpholino, lower alkylmorpholino, pyrrolidino, and loweralkylpyrrolidino radicals, which comprises interacting a compound havingthe formula o\ /H (|)OH2Y /GH2 with a compound having the formula YCnH2n-CON B Where one of Y and Y is halogen and the other is an aminoradical having the formula H-N(R).

13. A'process for the preparation of a 2-{N-[2-(N,N-

dialkylcarbarnyl ethyl] aminoethy1}-1,4-benzodioxan having the formulawhere R and R are lower alkyl radicals, which cornprises interactingZ-aminomethyl-l,4-benzodioxan with an N,N-di-loweralkyl-3-l1alopropionamicle.

7 -10 14. A process for the preparation of a 2-{N-[2-(N- loweralkylcarbamyl) ethyl] aminomethyl}-'1,4-benzodioxan having the formulawhere R is a lower alkyl radical, which comprises interactingZ-aminomethyl-l-4-benzodioxan with an N-lowe'r alkyl-3-halopropionamide.15. A process for the preparation of a compound of a 2-{N-loweralkyl-N-[2-(N,N-di-lower alkylcarba'myU-ethyl]aminomethyl}-1,4-benzodioxan having'the formula Hz R R where R, Rand R are lower alkyl radicals, which comprises interacting a 2-(loweralkylamin0methy1)-1,4- benzodioxan with an N,N-di-loweralkyl-3-halopropionamide.

1 6. A process for the preparation of a 2-{N-lower alkyl N- [2-(N-loweralkylcarbamyl)ethyl] aminomethyl}-l,4-benzodioxan having the formula HzR where R is a member of the class consisting of hydrogen and loweralkyl radicals, n is an integer of the group 1 to 3 inclusive, and -N=Bis a member of the group consisting of the amino radical and loweralkylamino, (di-lower alkyl)amino, piperidino, lower alkylpiperidino,morpholino, lower alkylmorpholino, pyrrolidino, and loweralkylpyrrolidino radicals, which comprises interacting a2-[H-N(R)-CH2-]-l,4-benzodioXan with a halolower fatty acylating agentof the group consisting of halo-lower fatty acyl halides and halo-lowerfatty acid anhydrides; and treating the 2-[N-(halo-lower fattyacyl)aminomethyl]-l,4-benzodioxan thus obtained with an aminating agenthaving the formula H-N=B.

18. A process for the preparation of a 2-[N-lower alkyl-N- (N,N-di-loweralkylaminoacetyl aminomethyl 1,4-benzodioxan having the formula where R,R and R are lower alkyl radicals, which comprises interacting a 2-(1oweralkylaminomethyl)-l,4- benzodioxan with a haloacetyl halide; andtreating the 2- (N-lower alkyl-N-haloacetyl) aminomethyl-1,4-benzodioxanthus obtained with a (di-lower alkyl)amine.

2,725,386 11 12 19.- A process for the preparation of a Z-{N-lower 21. 2{N [2-(N,N-dimethylcarbamy1)ethyllaminoalkyl-N-[3-(N,N-di-1oweralky1amin0)propionyl]aminomethyl}-1,4-benzodioxan, having the formulamethyl}-1,4-benzodioxan having the formula o 1=. R 5 7 CO (FCHECHPNC-CH:-NHCH:CH: N(CH3):

' H2 H1 R R 0 222322 2 g i zgg g i f f 8:22? 10 References Cited in thefile of this patent s 1 wera yam1no-,- dioxan with a 3-halopropionylhalide; and treatment of UNITED STATES PATENTS the 2-[N-lowera1kylN-(3-halopropionyl)aminomethyl} 2,056,046 Fourneau Sept. 29, 19361,4:benzodtoxan thus obtained with a (di-lower-a1kyl)- ,7 Br c et l-1953 amlne. I

20. 2-{ -[2- (N-methyloarparnyl)ethyllaminoethyl} FOREIGN PATENTS1,4-benzodioxan, having the formula 468,504 Canada Oct. 3, 1950 0 HCCHQNHCHr-CHFt1-Nfi-CH; OTHER REFERENCES (IJH, L t 20 MlkamxzvChem.Abst., vol. 33,001. .8315 (1939).

1. A COMPOUND HAVING THE FORMULA